Isoform selective HDAC inhibitors
View Patent ↗One aspect of the invention relates to isoform-selective HDAC inhibitors. Also provided are methods of sensitizing a cancer cell to the cytotoxic effects of radiotherapy. The invention also provides methods for treating cancer, methods for treating neurological diseases and methods for treating malaria. Additionally, the invention provides pharmaceutical compositions comprising an HDAC inhibitor of the invention; and kits comprising an HDAC inhibitor of the invention.
1. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of
2. A method of treating malaria, comprising the step of:
administering to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of
wherein
W is halo, azido, alkyl, fluoroalkyl, perfluoroalkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, amino, alkylamino, arylamino, acylamino, heteroarylamino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, acyl, carboxyl, oxycarbonyl, aryloxy, silyl, thioether, sulfo, sulfonate, sulfonyl, sulfonamido, formyl, cyano, or isocyano;
L is -(Q 1 )-N(H)C(═O)-(Q 2 )-Z;
Q 1 is C 1-3 alkylene or a bond;
Q 2 is C 1-10 alkylene;
Z is
and
the stereochemical configuration at any stereocenter is R, S, or a mixture of these configurations.
3. The method of claim 2 , further comprising co-administering to said subject an antimalarial compound selected from the group consisting of aryl amino alcohols, cinchona alkaloids, 4-aminoquinolines, type 1 or type 2 folate synthesis inhibitors, 8-aminoquinolines, antimicrobials, peroxides, naphthoquinones and iron-chelating agents.
4. The method of claim 2 , further comprising co-administering to said subject an antimalarial compound selected from the group consisting of quinine, quinidine, mefloquine, halofantrine, chloroquine, amodiaquine, proguanil, chloroproguanil, pyrimethamine, primaquine, 8-[(4-amino-1-methylbutyl)amino]-2,6-dimethoxy-4-methyl-5-[(3-trifluoromethyl)phenoxy]quinoline succinate (WR238,605), tetracycline, doxycycline, clindamycin, azithromycin, fluoroquinolones, artemether, arteether, artesunate, artelinic acid, atovaquone, and desferrioxamine.
5. The method of claim 2 , further comprising co-administering chloroquine to said subject.
6. The method of claim 2 , wherein said compound is
and further comprising co-administering chloroquine to said subject.
7. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.